Hyperbilirubinemia is probably the most frequent disease which is diagnosed and treated in the human newborn. Current treatment attempts to prevent neurologic damage. Treatment is base on the theory that free (unbound) bilirubin is the toxic fraction of the total bilirubin pool. Proof of this theory is lacking, and certain clinical and experimental findings are not consistent with the theory. Another hypothesis better explains the available data: bilirubin enters the brain bound to albumin when the blood-brain barrier opens. This hypothesis was tested experimentally. We showed that kernicterus does occur when the bloor-brain barrier was opened in jaundiced rats. This kernicterus resulted from the entry of albumin-bound bilirubin and not from the passage of free bilirubin. Since the barrier was opened on only one side of the brain, unilateral kernicterus resulted. This provides a convenient amimal model of kernicterus, since a control hemisphere is available in the same animal.